In the classical form of 11-antitrypsin (AT) deficiency a point mutation alters the folding of an abundant liver-derived secretory glycoprotein and also renders it prone to polymerization and aggregation. The mutant protein, 11-antitrypsin Z (ATZ), accumulates in the endoplasmic reticulum (ER) of liver cells. The 'chronic ER overload'state leads to hepatic fibrosis/cirrhosis and hepatocellular carcinoma by gain- of-toxic function mechanisms. Indeed, this deficiency is the most common genetic cause of liver disease in children and a relatively frequent cause of cirrhosis/carcinoma in adults. My lab has been studying the mechanisms by which hepatocytes activate pathways for intracellular disposal of the mutant ATZ with the hypothesis that variation in the function of these pathways might explain variation in incidence and severity of liver disease among homozygotes and, further, that these pathways might be targeted by potential pharmacotherapeutic strategies. We have found that the proteasome is responsible for degrading soluble forms of mutant ATZ and autophagy is specialized for disposal of the insoluble polymers and aggregates. Because of the importance of autophagy in the cellular response to accumulation of ATZ in the ER, we examined whether a drug that enhances autophagy could ameliorate hepatotoxicity in this disorder. From a list of drugs that have been recently shown to enhance autophagic degradation of aggregation-prone proteins with polyglutamine repeats, we selected carbamazepine (CBZ) for detailed studies of its effect on ATZ because it has the most extensive safety profile in humans. The results showed that CBZ dramatically increases degradation of mutant ATZ in cell line models of AT deficiency. Furthermore, when administered orally for 2 weeks to the PiZ mouse model of AT deficiency, CBZ decreased the hepatic load of ATZ in vivo and significantly reduced hepatic fibrosis. The overall objective of this proposal is to determine whether CBZ could be an effective treatment for liver disease due to AT deficiency in humans. Patients with compensated cirrhosis due to homozygous AT deficiency will be treated with CBZ for 12 months in a randomized, double-blinded, placebo-controlled trial. The overall hypothesis is that CBZ therapy will reduce the hepatic ATZ load by enhancing its intracellular degradation and, as a consequence, reduce hepatic fibrosis and portal hypertension. This hypothesis will be tested through the following specific aims: 1) Determine whether CBZ treatment reduces hepatic ATZ load in AT-deficient individuals with severe liver disease;2) Determine whether CBZ treatment reduces hepatic fibrosis in AT- deficient individuals with severe liver disease;3) Determine whether CBZ treatment reduces portal pressure in AT-deficient individuals with severe liver disease. The trial will also determine whether CBZ is tolerated by patients with severe liver disease without serious adverse effects. PUBLIC HEALTH RELEVANCE: This application proposes a clinical trial to determine whether carbamazepine can be used to treat severe liver disease due to 11-antitrypsin deficiency, the most common genetic disease for which children currently undergo liver transplantation.